PROJECT SUMMARY P1, WEBB Toll-like receptor 9 activation by mitochondrial DNA causes vascular injury in hypertension Hypertension affects over 75 million U.S. adults and plays a major role in the end organ damage commonly seen with cardiovascular diseases, including stroke, coronary artery disease, and ischemic nephropathy. Our proposal provides a new paradigm whereby activation of the innate immune system via mitochondrial DNA (mtDNA) leads to increased vasoconstriction, reduced vasodilation and vascular remodeling in hypertension. Understanding this mechanism may assist in the development of new drugs that target the immune system to treat vascular dysfunction and prevent the progression of hypertension. The research will be guided by the novel hypothesis that in hypertension, exaggerated vascular and tissue cell death give rise to mtDNA that trigger the innate immune response via Toll-like receptor 9 (TLR9) causing vascular inflammation, vasoconstriction, endothelial dysfunction and vascular remodeling. A rat model of hypertension [spontaneously hypertensive rat (SHR)] will be used and we will test our hypothesis by accomplishing three specific aims: 1) test the hypothesis that pharmacological inhibition of cell necrosis attenuates the development of vascular dysfunction in hypertension; 2) test the hypothesis that activation of TLR9 signaling causes endothelial dysfunction, potentiates vasoconstriction and contributes to arterial stiffening; and 3) test the hypothesis that mtDNA contributes to the development and maintenance of hypertension. The proposed studies, integrating physiological, pharmacological, biochemical, molecular and cellular techniques, will help to better understand the effects of blood pressure on vascular function, as well as the contribution of abnormal TLR9 activation to vascular dysfunction characteristic of hypertension.